A role for APP in Wnt signalling links synapse loss with β-amyloid production

Elliott, C. et al. (2018) A role for APP in Wnt signalling links synapse loss with β-amyloid production. Translational Psychiatry, 8, 179. (doi: 10.1038/s41398-018-0231-6) (PMID:30232325) (PMCID:PMC6145937)

Abstract

In Alzheimer’s disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by β-amyloid (Aβ) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-β-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aβ-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aβ production, while activation of canonical signalling suppresses Aβ production. Together, these findings identify a pathogenic-positive feedback loop in which Aβ induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aβ production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aβ production. Finally, we report that pharmacological inhibition of the Aβ-Dkk1-Aβ positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aβ load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aβ accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

• Item Type: Articles
• Additional Information: This work was supported by Medical Research Council grant MR/M013944/1, awarded to Killick. The Wolfson Drug Discovery Unit receives core support from the UK National Institute for Health Research Biomedical Research Centre and Unit Funding Scheme. The CIBERNED received funding from the Spanish Ministry of Economy and Competitiveness, award SAF2016-76520-R, and an MRC Centres of Excellence in Neurodegeneration (COEN) Pathfinder award, a part of the EU-Joint Program for Neurodegenerative diseases.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Elliott, Dr Christina and Baillie, Professor George
• Authors: Elliott, C., Rojo, A. I., Ribe, E., Broadstock, M., Xia, W., Morin, P., Semenov, M., Baillie, G., Cuadrado, A., Al-Shawi, R., Ballard, C. G., Simons, P., and Killick, R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Translational Psychiatry
• Publisher: Nature Publishing Group
• ISSN: 2158-3188
• ISSN (Online): 2158-3188
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Translational Psychiatry 8:179
• Publisher Policy: Reproduced under a Creative Commons License